# Inflammation-triggered self-immolative conjugates enable oral peptide delivery by overcoming gastrointestinal barriers

## TL;DR

A new strategy for oral delivery of peptides uses inflammation-responsive prodrug conjugates to improve stability and effectiveness in treating inflammatory diseases.

## Contribution

The SIPPC platform introduces a self-immolative conjugate that targets inflammation and enables oral peptide delivery.

## Key findings

- The SIPPC conjugates showed remarkable gastrointestinal stability and efficient mucus penetration.
- ProKPV achieved 3.8-fold greater colonic accumulation in colitis mice compared to free KPV.
- Oral proKPV also showed potent anti-inflammatory effects in mice with acute lung injury.

## Abstract

Oral delivery of peptide therapeutics remains challenging due to gastrointestinal (GI) degradation and poor intestinal absorption. Here, we propose a self-immolative peptide prodrug conjugate (SIPPC) platform for inflammation-targeted oral delivery, integrating a hydrophilic polyethylene glycol segment, a reactive oxygen species (ROS)–responsive hydrophobic self-immolative module, and a hydrolyzable scaffold, which collectively enable spontaneous assembly into micelle-like nanoparticles. Using three anti-inflammatory peptides (KPV, Ac-QAW, and IRW), we demonstrated that the engineered conjugates exhibit remarkable GI stability, efficient mucus penetration, and ROS-responsive release at inflamed sites. In colitis mice, the KPV-based conjugate (proKPV) achieved a 3.8-fold greater colonic accumulation than free KPV, with enhanced efficacy even at a 20-fold lower dose. Beyond therapeutic effects in the colitis model, oral proKPV substantially accumulated in inflamed lungs and exhibited potent anti-inflammatory efficacy in mice with acute lung injury. Ac-QAW and IRW-based conjugates exhibited comparable benefits, underscoring SIPPC as a transformative paradigm for oral peptide therapeutics, offering substantial promise for clinical translation in inflammatory disorders.

An inflammation-responsive, self-immolative prodrug conjugate strategy is developed for oral delivery of peptide therapeutics.